Project Summary/Abstract Research Summary: Long-term post-transplant outcomes remain suboptimal, especially for recipients of deceased donor organs. Building upon previous studies, our preliminary data from a murine heart transplant model implicate peri-transplant complement-mediated ischemia reperfusion (IR) injury and inflammation as a central mediator of increased alloimmunity and late graft failure/dysfunction. In this project we will study the mechanisms and effects of complement activation on IR-associated inflammation (Aim 1) and the mechanisms linking increased IR-induced complement-dependent inflammation to late post-transplant allospecific immunity and outcomes (Aim 2). These aims will test our central hypothesis that IR-injury induced inflammation is dependent upon recipient mannose binding lectin-dependent complement activation, that inflammation induces greater recipient APC activation/donor antigen acquisition, and that these primed APCs then foster a stronger adaptive anti- donor T cell response leading to graft rejection. The specific findings have the potential to identify novel therapeutic targets that can be translated to human trials to improve transplant outcomes. Environment: Both the Icahn School of Medicine at Mount Sinai and Division of Nephrology are firmly committed to junior faculty career development. Dr. Peter Heeger (mentor) is an established expert in the field of complement immunology and transplant research with a strong record of developing junior faculty into independent researchers. Candidate Training: The primary objective of this application is to support Dr. Nicholas Chun's career development into an independent researcher scientist in the field of complement immunobiology and human disease. Dr. Chun's proposed training activities are in four broad non-mutually exclusive areas: 1) Enhancement of fundamental knowledge (e.g. immunology, complement, and exosome biology); 2) Scientific Communication (e.g. manuscript/grant writing, presentation skills); 3) Practical skills (e.g. statistical analysis, large data set analysis, advanced imaging); 4) Managerial skills (e.g. lab finances, personnel administration). The general approaches and skills outlined during this award will form the basis for future research. !